GDMICP Streszczenie raportu

Final Report Summary - GDMICP (|Gestational signal and bile acid role in the enteroinsular axis)

Gestational diabetes is a form of diabetes that affects women only during pregnancy. Normally, glucose levels in the blood are controlled by insulin released by beta cells in the pancreas. However, during pregnancy, some women develop higher than normal levels of glucose in their blood, which insulin is not able to bring under control. Gestational diabetes usually develops in the third trimester (after 28 weeks) and in the majority of the cases disappears after the baby is born. However, women who develop gestational diabetes are more likely to develop type 2 diabetes later in life. The consequences of GDM extend beyond the mother, as human and animal studies have demonstrated that the the nutritional environment in the womb can have an impact on the developing baby. Adverse side effects include large for gestational age babies, which can be associated with fetal death, birth trauma, in addition to increased susceptibility of the these children to T2DM in later life. Globally, the clinical and financial burden of impaired glucose metabolism during pregnancy is severe as there are an estimated 55 million women of reproductive age at high risk of developing GDM, with the associated impact on the health of the mother, and her children in the womb and later on in life. On the other hand, cholestasis is a pathological state caused by a rapid or chronic interruption in the bile flow from the liver arising from either defects in hepatic bile formation and transport or from impairment in bile flow. Intrahepatic cholestasis of pregnancy (ICP) is characterised by the presence of pruritus (itch) and abnormal liver function tests with elevated bile acid levels, appearing usually during the third trimester of pregnancy and persisting until delivery. ICP is associated with adverse pregnancy outcomes, including increased rates of spontaneous preterm labour, fetal distress, prolonged neonatal unit admission, and perinatal mortality. As with GDM, the Williamson group have shown that that there is an association of ICP in the mother with an increased risk of subsequent obesity and increased blood lipids in the child. It has been demonstrated, also, that ICP women have increased susceptibility to develop GDM but the reasons are not fully understood. ICP is characterized by elevated bile acids and in the liver bile acid metabolism and synthesis is primarily regulated by the nuclear receptor FXR. A previous Marie Curie Fellow based in CW’s group also established the functional consequences of genetic variants of FXR identified in ICP patients. FXR is not only important for bile acid homeostasis but also for the regulation of glucose. TGR5 is another bile acid receptor that is involved in glucose metabolism. In the intestine, activation of TGR5 by bile acid leads to glucagon-like peptide 1 (GLP1) release by a particular type of intestinal cells called enteroendocrine cells. GLP1 belongs to the family of incretins, and its binding on pancreatic islets stimulates the rapid release of insulin from the beta cells. The fellow hypothesised that reproductive hormones and their metabolites play an integral role in glucose metabolism in pregnancy. Furthermore, it was suggested that aberrant bile acid homeostasis during ICP further contributes to the development of GDM, by interfering with FXR and TGR5 signalling in the gut and pancreas. Indeed, the fellow demonstrated an interesting role for some gestational hormones (metabolites of progesterone) that are greatly increased during pregnancy. The fellow analysed the levels of these metabolites of progesterone in pregnant women and found that individuals with high levels of glucose in their blood (more prone to develop GDM) had lower levels. Then, the fellow investigated whether these metabolites could can influence islet function and found that these metabolites were able to induce insulin secretion in isolated islets in vitro. It is also important to mention that during pregnancy beta cells increase their number forming bigger islets. This is an adaptive response to the progressive insulin resistance that occurs during gestation, and the development of GDM may reflect the outcome of a failure in this adaptation. In mid-to-late gestation, maternal food intake and fat deposition increase, and metabolism is significantly altered by the emergence of insulin resistance. The gestational metabolic adaptations are believed to be orchestrated by hormones that are secreted by the placenta and maternal pituitary gland. The elevation of maternal hormones coincides with the development of maternal insulin resistance. However, the increased insulin production is maintained throughout late gestation, providing tight control of glucose at physiological levels. The ability of progesterone metabolites to increase insulin secretion suggested that the elevation of hormones during pregnancy not only increases beta cell proliferation and expansion, but also insulin secretion in islets providing a useful feedback mechanism for higher insulin demand. Thus, these progesterone metabolites could be a useful biomarker to identify women with higher risk of developing GDM later during pregnancy. Moreover, the fellow demonstrated that progesterone metabolites did not promote insulin release through their known receptors, FXR and TGR5. The fellow also investigated the role of cholestasis in the development of GDM, finding that ICP women are more insulin resistant compared to women with uncomplicated pregnancy. However, beta cell function, in terms of insulin release, seemed to be normal. To investigate the effect of elevated bile acids on maternal glucose homeostasis, the fellow challenged wild type pregnant mice with a diet enriched with bile acids. Interestingly, physiological islet expansion and beta cell proliferation were reduced in pregnant mice fed with bile acids, while several beta cells were dying maybe because of the toxic effect of high concentrations of bile acids. It is worth mentioning that in this animal model the concentration of bile acids were very similar to severe cases of cholestasis in women, while the ICP women analysed in this study were less severe cases. Thus, the effect of bile acids on islet function may be dependent on the severity of the disease. In future, untreated severe ICP cases will provide the definite answer to this discrepancy. The fellow also investigated if a high bile acids together with Fxr ablation could be responsible for maternal glucose increase. Indeed, pregnant mice lacking Fxr showed impaired glucose tolerance and elevated insulin resistance. In other terms, once administered high quantity of glucose they were not able to reduce their blood glucose as efficiently as wild type animals. In addition, pancreatic islets lacking Fxr failed to expand and showed a decreased proliferation rate during pregnancy. Their islets were also unable to secrete adequate levels of insulin. Finally, the fellow interrogated the potential role of bile acids in the intestine (where bile acids are secreted to help digestion) and their influence on GLP-1 secretion. ICP women showed decreased GLP1 secretion after a standardised lunch. In line with human GLP-1 levels, mice lacking Tgr5, the bile acid receptor involved in GLP-1 secretion in enteroendocrine cells, showed impaired glucose tolerance and decreased insulin release. In addition, GLP-1 levels in these women were comparable to the levels in pregnant women with uncomplicated pregnancy. In summary, we have shown that ICP women had increased insulin resistance. In case of severe cholestasis as in mice lacking Fxr, the islet inability to expand together with increased insulin resistance caused severe maternal glucose intolerance, suggesting that FXR plays an important role in the association between ICP and GDM. Moreover, GLP-1 seemed to be an important contributor in this pathology, since women with ICP had lower level of this hormone and mice with reduced Glp-1 secretion had impaired glucose intolerance. Notably, UDCA treatment is able to increase GLP-1 secretion in ICP women, underlining the importance of treatment for ICP women.